Granzyme B is not required for regulatory T cell-mediated suppression of graft-versus-host disease

Regulatory T (T-reg) cells can suppress a wide variety of immune responses, including antitumor and alloimmune responses. The mechanisms by which T-reg cells mediate their suppressive effects depend on the context of their activation. We previously reported that granzyme B is important for T-reg cell-mediated suppression of antitumor immune responses. We therefore hypothesized that granzyme B may likewise be important for suppression of graft-versus-host disease (GVHD). We found that allogeneic mismatch induces the expression of granzyme B in mixed lymphocyte reactions and in a model of graft-versus-host disease (GVHD). However, wild-type and granzyme B-deficient T-reg cells were equally able to suppress effector T (T-eff) cell proliferation driven by multiple stimuli, including allogeneic antigen-presenting cells. Surprisingly, adoptive transfer of granzyme B-deficient T-reg cells prevented GVHD lethality, suppressed serum cytokine production in vivo, and prevented target organ damage. These data contrast strikingly with our previous study, which demonstrated that granzyme B plays a nonredundant role in T-reg cell-mediated suppression of antitumor responses. Taken together, these findings suggest that targeting specific T-reg cell-suppressive mechanisms, such as granzyme B, may be therapeutically beneficial for segregating GVHD and graft-versus-tumor immune responses. (Blood. 2010;115:1669-1677)